Monitoring the events taking place in fuel cell systems (and fuel cell materials) under operating conditions is crucial for understanding the reaction mechanisms of many important chemical processes (e.g., catalyst degradation, membrane breakdown) and physical processes (e.g., water transport and distribution), and would allow the rational design of new or better fuel cells and fuel cell materials (e.g., catalysts and membranes). Operando methodology combines the evaluation of new materials (activity, selectivity of catalysts; and hydration, conductivity of membranes) and fuel cell system performance (flow, distribution of water) in a single experiment. Operando methodologies appear as an excellent tool to assess the structure-reactivity relationships at a molecular scale since structural and catalytic parameters are determined simultaneously. Furthermore, studies of fuel cells under actual operating conditions allows for a detailed understanding of temperature, loading, and design.